Every year, rotavirus and *Shigella* together kill tens of thousands of children in low- and middle-income countries, yet no vaccine exists for *Shigella* and the rotavirus vaccines that do exist work poorly in these settings. The core problem is a missing piece of biological knowledge: researchers lack reliable "correlates of protection"—measurable immune signals that tell you whether a vaccine is actually working. Without these markers, developing better vaccines is like navigating without a compass. This project will identify those correlates by studying adults infected with rotavirus and *Shigella*, then confirm them in samples from vaccinated children. It will also fill a major gap in knowledge by documenting what causes diarrhoea in older adults, a group whose disease burden is poorly understood. If successful, the work could accelerate development of more effective enteric vaccines, improve how antibiotics are prescribed for diarrhoea in Malawi, and reduce the spread of antimicrobial resistance. The findings would directly inform vaccine policy and public health decisions in countries where diarrhoeal disease remains a leading killer.
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Over half of the annual childhood diarrhoea-associated mortalities and morbidities are attributed to rotavirus (128,000 deaths) and Shigella (90,000 deaths), particularly in LMICs. However, the causes of diarrhoea in older adults are less well-documented, and limited diagnostic services in LMICs such as Malawi have led to poor antimicrobial stewardship, with antibiotics often prescribed empirically to treat diarrhoea. Whilst vaccines are fundamental tools to effectively reduce the burden of enteric diseases, there are no licensed vaccines against Shigella, and those against rotavirus underperform in LMICs - highlighting the pressing need to develop more effective enteric vaccines. Correlates of Protection (CoP) against a virus or infectious pathogen are key measurable indicators that an individual has immunity against infection and/or disease progression. The absence of established CoP has been a barrier to advancing vaccine development for pathogens like Shigella and rotavirus. Leveraging my expertise in evolutionary biology and host immune responses to enteric pathogens, I plan to pursue three workstreams over the next five years. These include determining the aetiology and antimicrobial profiles of infectious diarrhoea in older adults, using rotavirus- and Shigella-infected adults as models to identify CoP, and validating these CoP in samples from vaccinated and infected children. Workstream 1 - Diarrheal Disease Burden: Examine the impact of rotavirus vaccine introduction on the epidemiology, transmission, and prevalence of all-cause diarrheal pathogens in children under 5 years since 2012. Additionally, characterise the aetiology of moderate to severe diarrhoea in adults over 50 years to better estimate aetiology-specific diarrheal deaths, document case fatality rates, and profile genetic antimicrobial resistance patterns of major bacterial pathogens contributing to diarrhoea in both children and adults. Workstream 2 - Host immunity: Examine humoral, innate and adaptive immune responses induced using high throughput techniques including systems serology, proteomics and immune repertoire sequencing to characterise protective immune signatures and CoP to rotavirus and Shigella. Workstream 3 - Prevention of enteric infection throughs vaccination: Evaluate the performance of already introduced or next generation (rotavirus), and new (Shigella) vaccines, and confirm the CoP identified in adults using samples collected from children. These workstreams will be complemented by three cross-cutting activities across the whole programme: Training: Support Malawian researchers to develop their research careers and become the next generation of leading scientists. Advocacy: Advocate, support and engage with the Malawi government and other stakeholders, towards continued use and introduction of new efficacious enteric vaccines. Communication with the public, practitioners and policy makers: I have developed this proposed work by considering the current needs and interests of relevant stakeholders through community feedback engagement activities. Relevant stakeholders will be engaged throughout to ensure their input and findings are timely implemented. Anticipated impact Profiling diarrhoea aetiology and their antimicrobial characteristics coupled with dissemination to key stakeholders would improve antimicrobial stewardship thereby reducing antibiotic resistance. Identification of CoP for rotavirus and Shigella would accelerate development of better and efficacious vaccines.
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